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United States Patent |
6,174,545
|
Enscore
,   et al.
|
January 16, 2001
|
Drug delivery devices and process of manufacture
Abstract
An improved process for manufacturing transdermal drug delivery devices and
devices made therefrom. The invention provides a heat equilibration
process for the manufacture of drug delivery devices which eliminates the
need to preload the body contacting layer with a drug. The method has
particular application in the manufacture of transdermal drug delivery
devices including a drug reservoir comprising drug in excess of
saturation.
Inventors:
|
Enscore; David J. (Sudbury, MA);
Campbell; Patricia S. (Palo Alto, CA);
Nedberge; Diane (Los Altos, CA);
Frame; Richard D. (San Diego, CA)
|
Assignee:
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Alza Corporation (Mountain View, CA)
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Appl. No.:
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243873 |
Filed:
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February 3, 1999 |
Current U.S. Class: |
424/448; 424/449; 514/691; 514/947; 602/41; 604/289; 604/304; 604/305; 604/307; 604/892.1 |
Intern'l Class: |
A61F 013/02 |
Field of Search: |
424/448,449
514/947,691
602/41
604/892.1,289,304,305,307
|
References Cited
U.S. Patent Documents
3598122 | Aug., 1971 | Zaffaroni | 128/268.
|
3598123 | Aug., 1971 | Zaffaroni | 128/155.
|
3742951 | Jul., 1973 | Zaffaroni | 128/268.
|
3797494 | Mar., 1974 | Zaffaroni | 128/268.
|
3854480 | Dec., 1974 | Zaffaroni | 128/260.
|
3938515 | Feb., 1976 | Leeper et al. | 128/260.
|
4031894 | Jun., 1977 | Urquhart et al. | 128/268.
|
4060084 | Nov., 1977 | Chandrasekaran et al. | 128/260.
|
4144317 | Mar., 1979 | Higuchi et al. | 424/21.
|
4201211 | May., 1980 | Chandrasekaran et al. | 128/268.
|
4379454 | Apr., 1983 | Campbell et al. | 604/897.
|
4588580 | May., 1986 | Gale et al. | 424/21.
|
4704282 | Nov., 1987 | Campbell et al. | 424/449.
|
4725439 | Feb., 1988 | Campbell et al. | 424/449.
|
4758434 | Jul., 1988 | Kydonieus et al. | 424/449.
|
4832953 | May., 1989 | Campbell et al. | 424/448.
|
4863970 | Sep., 1989 | Patel et al. | 514/784.
|
4867982 | Sep., 1989 | Campbell et al. | 424/449.
|
4908027 | Mar., 1990 | Enscore et al. | 424/443.
|
5004610 | Apr., 1991 | Osborne et al. | 424/448.
|
5152997 | Oct., 1992 | Ebert et al. | 424/449.
|
5164190 | Nov., 1992 | Patel et al. | 424/448.
|
5223262 | Jun., 1993 | Kim et al. | 424/448.
|
5344656 | Sep., 1994 | Enscore et al. | 424/448.
|
5508038 | Apr., 1996 | Wang et al. | 424/448.
|
5641504 | Jun., 1997 | Lee et al. | 424/447.
|
Foreign Patent Documents |
63-093714 | Apr., 1988 | JP.
| |
WO92/07590 | May., 1992 | WO.
| |
WO92/20377 | Nov., 1992 | WO.
| |
WO94/06383 | Mar., 1994 | WO.
| |
WO95/09006 | Apr., 1995 | WO.
| |
WO96/19205 | Jun., 1996 | WO.
| |
WO 96/35427 | Nov., 1996 | WO.
| |
WO 97/10812 | Mar., 1997 | WO.
| |
WO97/20550 | Jun., 1997 | WO.
| |
WO97/24148 | Jul., 1997 | WO.
| |
Other References
Cleary, Gary W., "Topical Drug Bioavailability, Bioequivalence, and
Penetration", Ch. 2, pp 17-68, Transdermal Delivery Systems: A Medical
Rationale, 1993.
Cleary, Gary W., "Skin Permeation Fundamental and Application", Ch. 11, pp
207-237, Transdermal Drug Delivery, 1993.
Govil, Sharad K., "Drug Delivery Devices Fundamental and Applications", Ch.
13 pp 385-419, Transdermal Drug Delivery Devices, 1988.
Chien, Y.W., S.T.P., Pharma Sciences 1 (1) 5-23 1991, Transdermal Systemic
Drug Delivery Recent Development and Future Prospects.
|
Primary Examiner: Clardy; S. Mark
Assistant Examiner: Williamson; Michael A.
Attorney, Agent or Firm: Date; Vandana, Bates; Owen J.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation of application Ser. No. 08/886,960,
filed Jul. 1, 1997, now abandoned which claims the priority of U.S.
Provisional application Ser. No. 60/021,124 filed on Jul. 3, 1996.
Claims
What is claimed is:
1. A device for the transdermal administration of testosterone through
intact, non-scrotal skin over an administration period comprising:
a) a backing layer;
b) a drug reservoir comprising a carrier and testosterone dispersed in
excess of saturation within the carrier;
c) a contact adhesive on the skin proximal side of the drug reservoir for
maintaining the device in testosterone-transmitting relation with intact,
non-scrotal skin, wherein the contact adhesive further comprises
testosterone dispersed in excess of saturation within the contact adhesive
at the beginning of the administration period,
wherein said excess in the drug reservoir is sufficient to maintain
testosterone at a level at or in excess of saturation in the drug
reservoir throughout a substantial portion of the administration period.
2. A device according to claim 1 further comprising a rate control membrane
on the skin proximal side of the drug reservoir.
3. A device according to claim 1 wherein the carrier comprises an aqueous
gel.
4. A device according to claim 3 wherein the carrier comprises ethanol.
5. A device according to claim 2 wherein the rate control membrane
comprises an ethylene vinyl acetate copolymer having a vinyl acetate
content of 5-30%.
6. A device according to claim 5 wherein the vinyl acetate content is
9-18%.
7. A device according to claim 1 wherein the adhesive comprises a blend of
low molecular weight polyisobutylene and high molecular weight
polyisobutylene.
8. A device according to claim 7 wherein the ratio of low molecular weight
polyisobutylene to high molecular weight polyisobutylene is 1.25:1.
Description
FIELD OF INVENTION
This invention relates to an improved process for the manufacture of drug
delivery devices and to drug delivery devices produced thereby. The
improvement comprises a heat equilibration process which controls the
migration of a drug from the drug reservoir through the adjoining layers
of the device. Preferably, this process enables improved control over the
concentration of the drug in the body contacting layer, such as the
contact adhesive layer of a transdermal device, resulting in greater
control of the initial loading dose of drug delivered by such devices. The
process has particular application in the manufacture of transdermal drug
delivery devices comprising a drug reservoir containing a drug at or above
saturation.
BACKGROUND OF THE INVENTION
Transdermal delivery devices for the delivery of a wide variety of drugs
have been known for some time. Typical devices range from simple
monolithic devices such as disclosed in U.S. Pat. No. 4,758,434, to
devices including in-line adhesives and release rate controlling membranes
as disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,742,951, 4,031,894,
4,060,084, 4,144,317, 4,201,211, and 4,379,454, all of which are
incorporated herein by reference. Such rate-controlled devices generally
comprise a backing layer which is impermeable to the drug, a drug
reservoir which can contain a permeation enhancer or permeation enhancer
mixture in addition to the drug, a contact adhesive layer, and a rate
controlling membrane positioned between the drug reservoir and contact
adhesive. The layers are typically laminated or heat sealed together to
produce a transdermal device.
It is known in the transdermal art to provide the drug reservoir with an
initial amount of drug at a concentration at or above its saturation
concentration in the reservoir in order to maintain a unit activity source
of the drug so that the delivery of drug from the device will remain
substantially constant over the intended delivery period. Subsaturated
systems, such as disclosed in U.S. Pat. Nos. 4,379,454, 4,908,027,
5,004,610, and 5,344,656, hereby incorporated in their entirety by
reference, are also known in the art.
In addition to providing the drug in the drug reservoir, it is also known
to preload the contact adhesive with an amount of the drug. For example,
U.S. Pat. Nos. 4,201,211, 4,588,580, and 4,832,953, hereby incorporated in
their entirety by reference, disclose transdermal drug delivery devices
wherein the contact adhesive layer is prepared by solvent casting a
mixture of the drug and adhesive. Typically, the preloaded amount
corresponds to the amount necessary to provide an initial loading dose
which creates a concentration gradient across skin and saturates the skin
binding sites underlying the device with the drug to be delivered.
Additionally, U.S. Pat. No. 4,832,953 discloses heating a laminate system
comprising a dispersion of a liquid in a non-aqueous matrix in order to
prevent formation of a crystalline hydrate.
In addition, Cleary "Transdermal Delivery Systems: A Medical Rationale",
Topical Drug Bioavailability, Bioequivalence, and Penetration, Plenum
Press 1993, pp 17-68, provides additional background information regarding
commercially available transdermal drug delivery systems. A reasonably
complete summary of the factors involved in percutaneous absorption of
drugs may be found in Govil, "Transdermal Drug Delivery Devices", Drug
Delivery Devices, Marcel Dekker, Inc. 1988, pp 385-419; Chien "Transdermal
Systemic Drug Delivery Recent Development and Future Prospects", S.T.P.
Pharma Sciences, Vol. 1, No. 1, pp 5-23, 1991; and Cleary "Transdermal
Drug Delivery", Skin Permeation Fundamentals and Application, pp 207-237,
1993, all of which are incorporated herein by reference.
The transdermal route of parenteral delivery of drugs provides many
advantages, and transdermal systems for delivering a wide variety of drugs
or other beneficial agents have been described. Steroids including
testosterone, for example, have been studied for their suitability for
transdermal delivery and transdermal drug delivery systems for delivering
testosterone are disclosed in the prior art. Current transdermal
testosterone systems can be generally classified as either scrotal or
non-scrotal systems. Each has its own advantages and disadvantages.
Scrotal systems such as described in U.S. Pat. Nos. 4,704,282, 4,725,439,
and 4,867,982, are more limited as to the available surface area for drug
delivery while, on the other hand, they do not require the use of
permeation enhancers. Non-scrotal systems such as described in U.S. Pat.
Nos. 5,152,997 and 5,164,990, while not as limited in area of application,
require the use of multiple permeation enhancers and are thus susceptible
to the problems attendant therewith, particularly irritation. Irritation
occurs as the skin reacts to topically applied substances, particularly
those maintained under occlusion, by blistering or reddening accompanied
by unpleasant burning, itching, and stinging sensations. It is desirable
to keep the number of possibly irritating substances in a transdermal
delivery device to a minimum.
More specifically, U.S. Pat. Nos. 4,704,282, 4,725,439, and 4,867,982,
which are hereby incorporated by reference in their entirety, disclose the
transdermal administration of testosterone through intact scrotal skin.
These patents teach that scrotal skin provides a five fold increase in
permeability to testosterone over non-scrotal skin. Testosterone is
provided in an ethylene vinyl acetate copolymer matrix and is delivered
through scrotal skin without the use of permeation enhancers.
U.S. Pat. Nos. 5,152,997 and 5,164,990, hereby incorporated in their
entirety by reference, disclose the transdermal administration of
testosterone through areas of intact, non-scrotal skin. The U.S. Pat. No.
5,164,990 patent requires an ethanol carrier and additionally includes a
permeation enhancer or permeation enhancer mixture such as glycerol
monooleate and methyl laurate in order to deliver therapeutically
effective amounts of testosterone through non-scrotal skin.
Additionally, U.S. Pat. No. 5,223,262 discloses a system for transdermally
delivering a hydrophobic alkanol soluble active agent to the skin at a
constant rate utilizing a lower alkanol penetration enhancer. The system
comprises an overlying solvent reservoir containing a lower alkanol
solvent and a drug reservoir containing an active agent in aqueous
alkanol. The two reservoirs are separated by a one way membrane permeable
to the alkanol solvent and substantially impermeable to the active agent
and water.
WO 96/35427, hereby incorporated in its entirety by reference, discloses a
transdermal therapeutic system for the delivery of testosterone which
comprises an alcoholic carrier saturated with testosterone and is free of
any permeation enhancers. The release rate of the active agent is
regulated by the adhesive layer.
WO 97/10812, hereby incorporated in its entirety by reference, discloses
methods for manufacturing transdermal drug delivery systems containing
supersaturated drug reservoirs which obtain higher drug fluxes. The method
involves heating the drug reservoir components to a predetermined
temperature and subsequently cooling the drug reservoir components in
order to provide a supersaturated reservoir such that it contains only a
single phase of drug and reservoir material.
As noted above, it is often desirable to preload the adhesive with an
amount of drug in excess of the saturation concentration and this has been
done by premixing the drug into the adhesive. However, the process of
premixing a drug into the adhesive layer, though enabling an amount of
drug in excess of saturation to be initially added to the adhesive,
presents considerable practical problems. The drug must be sent to the
adhesive supplier to be mixed with the adhesive and subsequently sent back
to the manufacturing site where the device is ultimately manufactured.
This requires undesirable shipping, time, and perhaps most significantly,
this process requires particular facilities at the site of the adhesive
supplier which conform with regulatory demands for the manufacture of drug
delivery devices.
DISCLOSURE OF THE INVENTION
According to this invention, we have eliminated the need to premix the body
contacting layer of a drug delivery device with the drug, while still
producing an end product having suitable amounts of drug in excess of
saturation in layers other than the drug reservoir, such as the contact
adhesive of a transdermal drug delivery device.
Accordingly, one aspect of the invention is to provide an improved method
of providing a drug delivery device with a loading dose.
Another aspect of the invention is to provide an improved process of
manufacturing drug delivery devices whereby a desired amount of drug may
be provided in the various layers of the drug delivery device and to
devices made therefrom.
Another aspect of the invention is to eliminate the need to preload the
contact adhesive of a transdermal drug delivery device with the drug in
order to obtain an end product having an amount of drug in excess of
saturation in the adhesive.
Another aspect of this invention is to provide an improved therapeutic
transdermal system for the delivery of testosterone through intact,
non-scrotal skin in order to achieve therapeutically effective blood
levels of testosterone in a patient.
These and other objects and advantages of this invention will be readily
apparent from the following description with reference to the accompanying
figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a cross-sectional view of one embodiment of the transdermal drug
delivery system according to this invention.
FIG. 2(a) is a cross-sectional view of one embodiment of a transdermal drug
delivery device prior to heat equilibration.
FIG. 2(b) is a cross-sectional view of one embodiment of a transdermal drug
delivery device during heat equilibration.
FIG. 2(c) is a cross-sectional view of one embodiment of a transdermal drug
delivery device after heat equilibration.
FIG. 3 depicts testosterone release rates from systems subjected to various
heat equilibration procedures.
FIG. 4 depicts the effect of exposure time at 40.degree. C. on the initial
fentanyl release rate from a transdermal device.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "drug" is to be construed in its broadest sense to
mean any material which is intended to produce some biological,
beneficial, therapeutic, or other intended effect, such as permeation
enhancement, for example, on the organism to which it is applied.
As used herein, the term "excess of saturation" refers to a condition
wherein drug exists in both a solid phase representing the excess and a
dissolved phase which is at saturation in the carrier.
As used herein, the term "loading dose" refers to the amount of drug
present in the adhesive layer or other body contacting layer other than
the drug reservoir in excess of the saturation concentration.
As used herein, the term "rapidly cooling" refers to a cooling process
which takes place over a period of time which is shorter than the period
of time at which the device is maintained at an elevated temperature and
preferably to a time period over which there is no subsequent
reequilibration of the drug containing layers.
As used herein, the term "substantial portion" refers to at least 60% of
the administration period.
As used herein, the term "therapeutically effective" refers to the amount
of drug or the rate of drug administration needed to effect the desired
therapeutic result.
As used herein, the term "transdermal" refers to the use of skin, mucosa,
and/or other body surfaces as a portal for the administration of drugs by
topical application of the drug thereto.
According to this invention, it has been discovered that a predetermined
amount of a drug can be introduced into layers of a drug delivery device
which are initially free of drug in excess of saturation, and the amount
thereof effectively controlled, by performing a heat equilibration process
wherein the device is subjected to an elevated temperature for a
predetermined period of time and thereafter rapidly cooled to ambient
conditions. The process enables a greater amount of drug to migrate at a
much quicker rate into the layers initially free of drug in excess of
saturation, such as the rate control membrane and adhesive layers of a
transdermal device, than is possible by simply allowing the device to
equilibrate at room temperature. The process also allows the layers
initially free of drug in excess of saturation to retain predetermined
amounts of drug in excess of saturation, after rapidly cooling to ambient
conditions. This process eliminates the need to mix the drug and body
contacting layer such as the adhesive layer of a transdermal delivery
device at a site other than the location of manufacture of the device in
order to provide a desired loading dose in the body contacting layer.
The process of the invention may be practiced so as to provide a desired
concentration of any drug in any of the particular layers of the final
system by selecting an appropriate drug loading in excess of saturation in
one of the layers of the device, usually the drug reservoir, and selecting
an appropriate time and temperature at which to conduct the heat
equilibration process. The temperature selected for the equilibration
process must be below that which causes degradation of the drug(s) or
which causes other deleterious effects such as undesirable phase changes
in the components of the device and is selected such that the drug remains
at least at saturation in the layer at the elevated temperature.
Temperatures useful in the present invention range from about
30.degree.-60.degree. C., preferably 35.degree.-45.degree. C. Once the
temperature is selected, the time may be varied anywhere from about 8
hours to 3 weeks, depending upon the desired loading dose of drug to be
delivered. A preferred range of times useful in the practice of the
present invention is between about 1 to 10 days.
After the heating process, the devices are rapidly cooled to ambient
conditions. The cooling step is performed such that drug is provided in
excess of saturation in the desired layer(s) of the device. Preferably,
the cooling process comprises subjecting the devices to a temperature
below the elevated temperature for a period of time less than that at
which the devices are subjected to the heating process. Preferred
temperatures for the rapid cooling are at ambient conditions and preferred
cooling times are from 6 hours to 5 days and most preferably from 6 to 36
hours.
This invention finds applicability with any type of drug delivery device
which utilizes a loading dose of drug in one of its layers. For example,
drug delivery systems such as those disclosed in U.S. Pat. Nos. 3,854,480
and 3,938,515, hereby incorporated in their entirety by reference, may be
used in the practice of this invention in order to provide the outer
polymeric membrane with a loading dose of drug.
A preferred embodiment of this invention is directed to controlling the
amount of drug migrating into the contact adhesive of a transdermal drug
delivery device. By controlling the amount of drug which migrates from the
drug reservoir into the contact adhesive, the initial loading dose of drug
delivered can be effectively controlled in order to achieve a desired
input of drug to saturate skin binding sites without requiring the drug to
be directly preloaded into the adhesive.
A particularly preferred embodiment is directed to transdermal drug
delivery devices for the administration of a drug at a substantially
constant rate throughout an intended administration period wherein the
drug reservoir contains drug at or in excess of saturation throughout the
delivery period. According to this particularly preferred embodiment, the
drug reservoir is initially provided with drug in excess of saturation and
the adhesive and rate control membrane are initially drug-free. During
heat equilibration the solubility of the drug in the reservoir and other
layers increases from that at ambient conditions and the other layers will
become saturated with the drug at this increased solubility level. After
the heat equilibration process and cooling of the device to ambient
conditions, the decrease in solubility of the other layers will cause
precipitation of the drug in excess of saturation which will then remain
in these other layers as a loading dose. The initial loading of drug in
the reservoir is preferably selected so that the reservoir remains
saturated with drug throughout the entire process.
Practice of this invention avoids the problems of preloading drug directly
into the adhesive and provides an amount of drug in the adhesive greater
than that possible from equilibration at normal conditions. Additionally,
providing the drug reservoir and the contact adhesive each with drug at or
in excess of saturation helps to prevent back flux of drug from the
contact adhesive to the drug reservoir.
In accordance with the particularly preferred embodiment, the inventors
have also discovered that testosterone may be effectively transdermally
administered to hypogonadal males through non-scrotal skin with a lower
incidence of skin irritation from a device of this invention comprising an
amount of testosterone in excess of its saturation concentration in an
ethanol carrier without additional permeation enhancers. Approximately 5-6
mg of testosterone may be transdermally delivered over 24 hours in order
to achieve a mean serum testosterone concentration in hypogonadal males
above the low end of the normal range for men (275-300 ng/dL) and a mean
maximum testosterone concentration at the mid-normal range of about
500-600 ng/dL. This is contrary to the teachings of U.S. Pat. Nos.
5,152,997 and 5,164,990 which suggest the need to provide testosterone at
a condition below saturation together with permeation enhancers in
addition to ethanol in order to achieve effective testosterone
concentrations by transdermal administration through non-scrotal skin.
Furthermore, the ethanol and testosterone are provided in a single
reservoir, thus simplifying the manufacture of the device.
Referring now to FIG. 1, a drug delivery device 10 comprising an aqueous
gel reservoir 2 according to this invention is shown. Delivery device 10
comprises a backing member 3 which serves as a protective cover for the
device, imparts structural support, and substantially keeps components in
device 10 from escaping the device. Device 10 also includes reservoir 2,
which contains the drug with or without a permeation enhancer, and bears
on its surface distant from backing member 3, a rate-controlling membrane
4 for controlling the release of drug and/or permeation enhancer from
device 10. The outer edges of backing member 3 overlay the edges of
reservoir 2 and are joined along the perimeter with the outer edges of the
rate-controlling membrane 4 in a fluid-tight arrangement. This sealed
reservoir may be effected by pressure, fusion, adhesion, an adhesive
applied to the edges, or other methods known in the art. In this manner,
reservoir 2 is contained wholly between backing member 3 and
rate-controlling membrane 4. On the skin-proximal side of rate-controlling
membrane 4 are an adhesive layer 5 and a strippable liner 6 which would be
removed prior to application of the device 10 to the skin.
According to the particularly preferred embodiment, the drug reservoir 2 is
initially provided with a drug loading comprising an excess amount of drug
beyond the saturation concentration of the drug in the reservoir such
that, after heat equilibration according to this invention, the reservoir
is maintained at a condition at or above saturation throughout a
substantial portion of the predetermined drug administration period. This
provides that the system will contain sufficient drug to provide the
contact adhesive with the desired loading dose of drug during the heat
equilibration and that the drug reservoir will contain sufficient drug in
order to achieve the desired serum concentration levels for the intended
period of administration. Additionally, maintaining the drug reservoir at
or in excess of saturation provides for a substantially constant rate of
administration.
To effect the heat equilibration process of this invention according to
this particularly preferred embodiment, the drug delivery device with the
drug reservoir comprising drug in excess of saturation is subjected to an
elevated temperature for a predetermined period of time. FIG. 2(a) depicts
drug delivery device 20 with excess drug 21 in the drug reservoir 22 as it
is provided prior to heat equilibration. The device 20 also comprises
backing 23, rate control membrane 24, contact adhesive 25, and release
liner 26. Upon heating the device 20 to the predetermined temperature the
solubility of the drug in all of the layers increases. Therefore, as long
as the drug reservoir layer remains saturated with drug during the
predetermined time period, drug migrates from the drug reservoir into the
adjoining layers 24 and 25 of the device at an accelerated rate due to the
shift in equilibrium, as depicted in FIG. 2(b). The shift in equilibrium
also allows for a greater amount of drug to migrate into the adjoining
layers, such as the contact adhesive 25, due to the increased solubility
of the drug in the adhesive at the elevated temperature. After the
predetermined time period, the device is removed from the elevated
temperature and allowed to cool to ambient conditions. As the temperature
decreases, the solubility of the drug in the adhesive also decreases,
leaving an amount of drug 21 in excess of saturation in the contact
adhesive at ambient conditions, as depicted in FIG. 2(c).
The amount of drug present in the therapeutic drug delivery device and
required to achieve an effective therapeutic result depends on many
factors, such as the minimum necessary dosage of the drug of the
particular indication being treated; the solubility and permeability of
the carrier and adhesive layer; and the period of time for which the
device will be fixed to the skin. The minimum amount of drug is determined
by the requirement that sufficient quantities of drug must be present in
the device to maintain the desired rate of release over the given period
of application. The maximum amount for safety purposes is determined by
the requirement that the quantity of drug present does not produce toxic
effects. Generally, the maximum concentration is determined by the amount
of drug that can be received in the carrier without producing adverse
histological effects such as irritation, an unacceptably high initial
loading dose of drug into the body, or adverse effects on the
characteristics of the delivery device such as the loss of tackiness,
viscosity, or deterioration of other properties.
The initial loading of drug in the carrier will determine the useful life
of the device, typically from 8 hours to seven days. The invention can be
used for such time periods, however, certain preferred embodiments are
particularly adapted for administration periods of up to about 24 hours.
As discussed with respect to the particularly preferred embodiment, the
drug is initially present in the carrier at a concentration at or in
excess of saturation. The drug may, however, be present at a level below
saturation during use without departing from this invention as long as the
drug is continuously administered to the skin or mucosal site in an amount
and for a period of time sufficient to provide the desired therapeutic
rate.
The backing may be a breathable or occlusive material including, but not
limited to, polyethylene, polyurethane, polyester or ethylene vinyl
acetate films. A polyethylene terephthlate/ethylene vinyl acetate backing
is preferred. If an ethylene vinyl acetate is employed as the backing,
preferably, it has a vinyl acetate content of 33% or 40%.
The rate-controlling membrane may be fabricated from permeable,
semipermeable or microporous materials which are known in the art to
control the rate of agents into and out of delivery devices and having a
permeability to the permeation enhancer lower than that of drug reservoir
12. Suitable materials include, but are not limited to, polyethylene,
polypropylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene
vinyl acetate copolymers. The rate control membrane may also include an
amount of mineral oil or other diffusive medium as disclosed in U.S. Pat.
No. 3,797,494, herein incorporated by reference in its entirety.
The reservoir formulation may be aqueous or non-aqueous based. Aqueous
formulations typically comprise water or water/ethanol and about 1-5 wt %
of a gelling agent, an example being a hydrophilic polymer such as
hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels
are comprised of silicone fluid or mineral oil. Mineral oil-based gels
also typically contain 1-2 wt % of a gelling agent such as colloidal
silicon dioxide. The suitability of a particular gel depends upon the
compatibility of its constituents with the drug and the
permeation-enhancing mixture, if used, in addition to any other components
in the formulation.
When using a non-aqueous based formulation, the reservoir matrix is
preferably composed of a hydrophobic polymer. Suitable polymeric matrices
are well known in the transdermal drug delivery art, and examples are
listed in the above-named patents previously incorporated herein by
reference. A typical laminated system would consist essentially of a
polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA)
copolymers, such as those described in U.S. Pat. No. 4,144,317, preferably
having a vinyl acetate (VA) content in the range of from about 9% up to
about 60% and more preferably about 9% to 40% VA. Polyisobutylene/oil
polymers containing from 4-25% high molecular weight polyisobutylene and
20-81% low molecular weight polyisobutylene with the balance being an oil
such as mineral oil or polybutene may also be used as the matrix material.
Suitable adhesives are well known in the art and include, but are not
limited to, silicone and/or acrylate polymers including mixtures and graft
copolymers thereof, polyisobutylene (PIB) adhesives comprising mixtures of
low and high molecular weight PIB's and an optional amount of mineral oil
or polybutene, such as those described in U.S. Pat. No. 5,508,038, herein
incorporated in its entirety by reference, styrene-butadiene copolymers,
and styrene-isoprene copolymers with tackifier(s).
Although any drug which is suitable for transdermal administration can be
delivered according to this invention, certain drugs are particularly
suited for administration from devices according to this invention.
Testosterone and its esters constitute a preferred drug for delivery
according to this invention, particularly for use in the treatment of
hypogonadic males. Other preferred drugs include hormones, particularly
steroids, estrogens such as estradiol and its esters, anabolic agents such
as nandrolone and its esters, progestogens such as progesterone and its
esters, corticosteroids, and narcotic agents.
The surface area of the device of this invention can vary from about 5
cm.sup.2 to about 75 cm.sup.2. A typical device, however, will have a
surface area within the range of about 20-60 cm.sup.2. A typical
transdermal device according to this invention is fabricated as an
approximately 60 cm.sup.2 generally elliptical or rectangular patch with
rounded corners.
The drug delivery devices of this invention may also contain other
permeation enhancers, stabilizers, dyes, diluents, pigments, carriers,
inert fillers, antioxidants, excipients, gelling agents, anti-irritants,
vasoconstrictors, as are known to the art.
The devices of this invention can be designed to effectively deliver drug
for an extended period of time from several hours up to seven days or
longer. Seven days is generally the maximum time limit for application of
a single device because the adverse effect of occlusion of a skin site
increases with time and a normal cycle of sloughing and replacement of the
skin cells occurs in about seven days.
According to the particularly preferred embodiment for the transdermal
administration of testosterone, the drug reservoir comprises 20-30 wt %
testosterone, 68-80 wt % ethanol, and 1-2 wt % of a gelling agent such as
hydroxypropyl cellulose, the rate control membrane comprises an ethylene
vinyl acetate copolymer having a vinyl acetate content of 5-30 wt %,
preferably 9-18%, and the adhesive comprises a polyisobutylene mixture
comprising high molecular weight PIB/low molecular weight PIB/mineral oil
in a ratio of 0.75-1.25/1-1.5/1.5-2.5, most preferably 1/1.25/2.
The aforementioned patents describe a wide variety of materials which can
be used for fabricating the various layers and components of the drug
delivery devices according to this invention. This invention, therefore,
contemplates the use of materials other than those specifically disclosed
herein, including those which may hereafter become known to the art and to
be capable of performing the necessary functions.
The following examples are offered to illustrate the practice of the
present invention and are not intended to limit the invention in any
manner.
EXAMPLE 1
Transdermal delivery systems for the administration of testosterone through
non-scrotal skin were made as follows. A reservoir gel comprising 26 wt. %
testosterone, 1-2 wt. % hydroxypropyl cellulose, and the remainder 95%
ethanol was prepared by mixing testosterone, 95% ethanol and adding
hydroxypropyl cellulose with mixing. The gel loading was 21 mg
testosterone/cm.sup.2.
A contact adhesive composition was made by mixing polyisobutylene (MW
1200000), polyisobutylene (MW 35000) and light mineral oil in a weight
ratio of 1:1.25:2. A 50 micron thick layer of the contact adhesive was
cast onto a 75 micron thick film of siliconized polyethylene terephthalate
release liner. The contact adhesive side of the resulting two layer
subassembly was laminated to a 50 micron thick film of ethylene vinyl
acetate (EVA) copolymer (9% vinyl acetate). The gelled
testosterone-ethanol mixture was placed on the EVA membrane. A backing
member comprised of aluminized polyethylene terephthalate with an EVA heat
sealable coating was laid over the gels and heat-sealed to the EVA
copolymer using a rotary heat seal machine. Finished systems were punched
from laminate using a circular punch and placed in sealed pouches to
prevent loss of volatile components.
Systems were then subjected to 35.degree. C., 40.degree. C., or 50.degree.
C. for a seven day period and release rates were tested at room
temperature and compared with systems kept at room temperature for 1 month
in order to observe the effect of temperature on the loading dose.
The release liner of the laminate was removed and the system was then
mounted on a Teflon.RTM. rod. A known volume of receptor solution (0.10%
phenol/H.sub.2 O) was then placed in a test tube and was equilibrated at
35.degree. C. The Teflon rod with the attached system was then placed in a
water bath at 35.degree. C. Mixing was accomplished by attachment to a
motor which caused constant vertical mixing.
At given time intervals, the entire receptor solution was removed from the
test tubes and replaced with an equal volume of fresh receptor solutions
previously equilibrated at 35.degree. C. The receptor solutions were
stored in capped vials at 4.degree. C. until assayed for testosterone
content by HPLC. From the drug concentration and the volume of the
receptor solutions, the area of permeation and the time interval, the flux
of the drug was calculated as follows: (drug concentration X volume of
receptor)/(area x time)=flux (.mu.g/cm.sup.2.cndot.hr).
FIG. 3 shows the effect of heat equilibration on the testosterone release
rate. From the results depicted in FIG. 3, it is seen that temperature
demonstrated the most significant effect on testosterone release rate
during the 0-2 hour initial delivery period, which corresponds to the
delivery of the loading dose. The loading dose for this system corresponds
approximately to the cumulative release of testosterone during the 0-2
hour period. The effect of heat equilibration on the loading dose, as
measured by the cumulative release of testosterone during the 0-2 hour
period, is shown in Table 1. As seen in Table 1, the loading dose
increased with the temperature of the heat equilibration process.
TABLE 1
Effect of Heat Equilibration
On Loading Dose of Testosterone
Group 0-2 Hour Cumulative Release (.mu.g/cm.sup.2)
I 6.7
II 26.0
III 28.2
IV 46.8
Group I was stored at room temperature for 1 month.
Group II was placed in oven at 35.degree. C. for 7 days.
Group III was placed in oven at 40.degree. C. for 7 days.
Group IV was placed in oven at 50.degree. C. for 7 days.
EXAMPLE 2
Transdermal therapeutic systems comprising an aqueous ethanolic gel were
prepared according to the following procedure. Fentanyl base was added to
95% ethanol and stirred to dissolve the drug. Purified water was then
added to generate a mixture containing 14.7 mg/g of fentanyl in a 30%
ethanol-water solvent. 2% of hydroxyethyl cellulose gelling agent was
added slowly to the solution with stirring and mixed until a smooth gel
was obtained (approximately 1 hour). A 0.05 mm thick contact adhesive
layer was formed on a fluorocarbon-diacrylate treated polyester film which
comprised the release liner for the system by solution casting an amine
resistant silicone medical adhesive onto the polyester film from a
solution in trichlortrifluorethane. A 0.05 mm thick rate controlling
membrane comprised of EVA (9% VA) was pressure laminated to the exposed
adhesive. A backing member comprised of a multilaminate of polyethylene,
aluminum, polyester, and EVA was also provided and the aqueous gel pouched
between the backing member and the release liner/adhesive/rate controlling
membrane on a rotary heat-seal machine at a gel loading of 15 mg/cm.sup.2.
Sealed pouches in sizes of 10 cm.sup.2 were die cut and immediately
pouched to avoid loss of ethanol.
The effect of heat equilibration on 10 cm.sup.2 systems prepared according
to the above procedure was tested. Systems were subjected to various
temperature/time regimens and thereafter kept at 25.degree. C. The
cumulative release of fentanyl during the initial 0-2 hour period was
measured using the procedure set forth in Example 1 to test release rates.
The release rates were measured after storage at 25.degree. C. for two
months. The results are shown in Table 2.
TABLE 2
Effect of Heat Equilibration on Fentanyl Loading Dose
0-2 hr release
Group (.mu.g/hr)
I 208.9
II 246.3
III 404.2
IV 445.1
Group I was placed in oven at 30.degree. C. for 7 days before storage at
25.degree. C.
Group II was placed in oven at 40.degree. C. for 3 days before storage at
25.degree. C.
Group III was placed in oven at 51.degree. C. for 1 day before storage at
25.degree. C.
Group IV was placed in oven at 60.degree. C. for 1 day before storage at
25.degree. C.
Table 2 shows that the cumulative release of drug during the initial 0-2
hour period of administration increases as the temperature of the heat
equilibration process increases. This initial 0-2 hour delivery period
corresponds approximately to the delivery of the loading dose. After 2
months storage at room temperature, no detectable movement of fentanyl
back into the drug reservoir from the adhesive was observed. It is seen
from Table 2 that the release of fentanyl during the 0-2 hour period
(loading dose) increases with temperature of heat equilibration.
EXAMPLE 3
The effect of exposure time at an elevated temperature heat equilibration
process was investigated. Systems prepared according to Example 2 were
kept at 40.degree. C. and release rates were taken at 0, 3, 7, and 14 day
intervals. FIG. 4 shows the effect of storage at 40.degree. C. on the
initial release of fentanyl during the 0-2 hour period (loading dose)
after delivery is initiated. As seen in FIG. 4, the loading dose increased
with time of exposure.
EXAMPLE 4
10 cm.sup.2 systems were prepared according to Example 2. Some of these
systems were subjected to 40.degree. C. for four days, while the remaining
systems were kept at room temperature. In vitro release profiles using the
procedure set forth in Example 1 were determined for each set of systems.
The average loading dose for these systems, measured by the 0-2 hour
cumulative release, was determined to be 199.00 .mu.g/hr for the room
temperature systems and 282.25 .mu.g/hr for the systems kept at 40.degree.
C. for four days. An amount of solid drug was observed in the drug
reservoir gel of each set of systems before performing the release rate
tests, indicating that the drug reservoir comprised an amount of drug in
excess of saturation. Solid drug was observed in the drug reservoir gel of
the heat equilibrated systems as they were removed from the oven.
Although the above examples have described the process as being performed
on pouched systems it is also possible to perform this process prior to
either system punching or pouching in those cases where there are no
concerns about loss of volatile components.
The invention has been described in detail with particular reference to
certain preferred embodiments thereof, but it will be understood that
variations and modifications can be affected within the scope and spirit
of the
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